复制压力是基因不稳定性的主要原因，也是癌细胞的关键弱点。这种弱点可以通过抑制 DNA 损伤响应与细胞周期控制相关联的激酶，包括 ATR、CHK1、WEE1 和 MYT1 检查点激酶，来进行治疗性靶向。此外，抑制 DNA 损伤响应会释放 DNA 片段到细胞质，从而引发固有免疫反应。因此，几种 ATR、CHK1、WEE1 和 MYT1 抑制剂正在接受临床评估，作为单一治疗或与化疗、聚[腺苷酸-核糖基]聚合酶 (PARP) 抑制剂或免疫检查点抑制剂联合应用，以利用高度的复制压力，克服治疗抵抗和促进有效的抗肿瘤免疫。在这里，我们回顾了针对癌症中复制压力的目前和新兴方法，从基础研究和生物标志物开发到临床试验评估。©2022.Springer Nature Limited。

Replication stress is a major cause of genomic instability and a crucial vulnerability of cancer cells. This vulnerability can be therapeutically targeted by inhibiting kinases that coordinate the DNA damage response with cell cycle control, including ATR, CHK1, WEE1 and MYT1 checkpoint kinases. In addition, inhibiting the DNA damage response releases DNA fragments into the cytoplasm, eliciting an innate immune response. Therefore, several ATR, CHK1, WEE1 and MYT1 inhibitors are undergoing clinical evaluation as monotherapies or in combination with chemotherapy, poly[ADP-ribose]polymerase (PARP) inhibitors, or immune checkpoint inhibitors to capitalize on high replication stress, overcome therapeutic resistance and promote effective antitumour immunity. Here, we review current and emerging approaches for targeting replication stress in cancer, from preclinical and biomarker development to clinical trial evaluation.© 2022. Springer Nature Limited.